Novel 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives and their medical use

ABSTRACT

This invention relates to novel 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives of formula (I) and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

TECHNICAL FIELD

This invention relates to novel 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivatives and their use in the manufacture of pharmaceuticalcompositions. The compounds of the invention are found to be cholinergicligands at the nicotinic acetylcholine receptors and modulators of themonoamine receptors and transporters.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

BACKGROUND ART

The endogenous cholinergic neurotransmitter, acetylcholine, exert itsbiological effect via two types of cholinergic receptors, the muscarinicAcetyl Choline Receptors (mAChR) and the nicotinic Acetyl CholineReceptors (nAChR).

As it is well established that muscarinic acetylcholine receptorsdominate quantitatively over nicotinic acetylcholine receptors in thebrain area important to memory and cognition, and much research aimed atthe development of agents for the treatment of memory related disordershave focused on the synthesis of muscarinic acetylcholine receptormodulators.

Recently, however, an interest in the development of nAChR modulatorshas emerged. Several diseases are associated with degeneration of thecholinergic system i.e. senile dementia of the Alzheimer type, vasculardementia and cognitive impairment due to the organic brain damagedisease related directly to alcoholism. Indeed several CNS disorders canbe attributed to a cholinergic deficiency, a dopaminergic deficiency, anadrenergic deficiency or a serotonergic deficiency.

WO 2005/074940 describes diazabicyclononyl phenyl-, pyridinyl-,pyridazinyl- and thiadiazolyl-derivatives useful as modulators of thenicotinic and/or of the monoamine receptors. However, thediazabicyclononyl pyrimidine derivatives of the present invention havenever been disclosed.

SUMMARY OF THE INVENTION

The present invention is devoted to the provision novel modulators ofthe nicotinic and/or of the monoamine receptors, which modulators areuseful for the treatment of diseases or disorders related to thecholinergic receptors, and in particular the nicotinic acetylcholinereceptor (nAChR), the serotonin receptor (5-HTR), the dopamine receptor(DAR) and the norepinephrine receptor (NER), and of the biogenic aminetransporters for serotonin (5-HT), dopamine (DA) and norepinephrine(NE).

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

The compounds of the invention may also be useful as diagnostic tools ormonitoring agents in various diagnostic methods, and in particular forin vivo receptor imaging (neuroimaging), and they may be used inlabelled or unlabelled form.

In its first aspect the invention provides novel1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives of Formula I

-   -   a stereoisomer thereof or a mixture of its stereoisomers, or a        pharmaceutically acceptable salt thereof; wherein    -   X represents N or CH; and    -   R¹ and R², independently of each other, represent hydrogen,        halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,        alkoxy, alkyl-sulfonyl, phenyl or phenoxy.

In its second aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of the1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives of the invention, astereoisomer thereof or a mixture of its stereoisomers, or apharmaceutically-acceptable salt thereof, together with at least onepharmaceutically-acceptable carrier or diluent.

In a further aspect the invention relates to the use of the1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives of the invention, astereoisomer thereof or a mixture of its stereoisomers, or apharmaceutically-acceptable salt thereof, for the manufacture of apharmaceutical composition/medicament for the treatment, prevention oralleviation of a disease or a disorder or a condition of a mammal,including a human, which disease, disorder or condition is responsive tomodulation of cholinergic receptors and/or monoamine receptors.

In a final aspect the invention provides methods of treatment,prevention or alleviation of diseases, disorders or conditions of aliving animal body, including a human, which disorder, disease orcondition is responsive to modulation of cholinergic receptors and/ormonoamine receptors, which method comprises the step of administering tosuch a living animal body in need thereof a therapeutically effectiveamount of the 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives ofthe invention.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

1,4-Diaza-bicyclo[3.2.2]nonyl Pyrimidine Derivatives

In a first aspect novel 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivatives are provided. The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivatives of the invention may be represented by the general Formula I

-   -   a stereoisomer thereof or a mixture of its stereoisomers, or a        pharmaceutically acceptable salt thereof; wherein    -   X represents N or CH; and    -   R¹ and R², independently of each other, represent hydrogen,        halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,        alkoxy, alkyl-sulfonyl, phenyl or phenoxy.

In a preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivative of the invention is a compound represented by Formula Ia

-   -   a stereoisomer thereof or a mixture of its stereoisomers, or a        pharmaceutically acceptable salt thereof; wherein    -   X represents N or CH; and    -   R¹ represents hydrogen, halo, trifluoromethyl, trifluoromethoxy,        cyano, nitro, alkyl-sulfonyl, phenyl or phenoxy.

In another preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention is a compound represented byFormula I or Ia, a stereoisomer thereof or a mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Xrepresents N or CH.

In a third preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention is a compound represented byFormula I or Ia, a stereoisomer thereof or a mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Xrepresents N.

In a fourth preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention is a compound represented byFormula I or Ia, a stereoisomer thereof or a mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Xrepresents CH.

In a fifth preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention is a compound represented byFormula I, a stereoisomer thereof or a mixture of its stereoisomers, ora pharmaceutically acceptable salt thereof, wherein R¹ and R²,independently of each other, represent hydrogen, halo, trifluoromethyl,trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, alkyl-sulfonyl, phenylor phenoxy.

In a more preferred embodiment one of R¹ and R² represents hydrogen; andthe other one of R¹ and R² represents hydrogen, halo, trifluoromethyl,trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, alkyl-sulfonyl, phenylor phenoxy.

In another more preferred embodiment one of R¹ and R² representshydrogen; and the other one of R¹ and R² represents halo,trifluoromethyl or alkoxy.

In a third more preferred embodiment R¹ represents hydrogen, halo,trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy,alkyl-sulfonyl, phenyl or phenoxy; and R² represents hydrogen.

In a fourth more preferred embodiment R¹ represents hydrogen, halo,trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl-sulfonyl, phenylor phenoxy; and R² represents hydrogen.

In a fifth more preferred embodiment R¹ represents halo,trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl-sulfonyl, phenylor phenoxy; and R² represents hydrogen.

In a sixth more preferred embodiment R¹ represents hydrogen, halo,trifluoromethyl or alkoxy; and R² represents hydrogen.

In a seventh more preferred embodiment R¹ represents hydrogen, halo ortrifluoromethyl; and R² represents hydrogen.

In an eighth more preferred embodiment R¹ represents hydrogen or alkoxy,and in particular methoxy; and R² represents hydrogen.

In a ninth more preferred embodiment R¹ and R² both represent hydrogen.

In a tenth more preferred embodiment R¹ represents alkoxy, and inparticular methoxy; and R² represents hydrogen.

In a most preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention is

-   -   3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-quinazolin-4-one;    -   3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-benzo[d][1,2,3]triazin-4-one;    -   3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-quinazolin-4-one;        or    -   3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-benzo[d][1,2,3]triazin-4-one;    -   a stereoisomer thereof or a mixture of its stereoisomers, or a        pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments described herein isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkoxy group designates an“alkyl-O-” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy groups of the invention include methoxy, ethoxy andisopropoxy.

In the context of this invention halo represents fluoro, chloro, bromoor iodo. Thus a trihalomethyl group represents e.g. a trifluoromethylgroup, a trichloromethyl group, and similar trihalo-substituted methylgroups.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomeric forms,including enantiomers, diastereomers, as well as geometric isomers(cis-trans isomers). The invention includes all such stereoisomers andany mixtures thereof including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is—in the case the compound beinga chiral acid—by use of an optically active amine, and liberating thediastereomeric, resolved salt by treatment with an acid. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L- (tartrates, mandelates,or camphorsulphonate) salts for example.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optically activestarting materials or intermediates.

Pharmaceutically Acceptable Salts

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the inventionmay be provided in any form suitable for the intended administration.Suitable forms include pharmaceutically (i.e. physiologically)acceptable salts, and pre- or prodrug forms of the compound of theinvention.

Examples of pharmaceutically acceptable salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of the invention and its pharmaceuticallyacceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the inventioninclude, without limitation, the sodium, the potassium, the calcium, themagnesium, the zinc, the aluminium, the lithium, the choline, thelysine, and the ammonium salt, and the like, of a compound of theinvention containing an anionic group. Such cationic salts may be formedby procedures well known and described in the art.

Additional examples of pharmaceutically acceptable salts include,without limitation, the non-toxic inorganic and organic acid additionsalts such as the hydrochloride, the hydrobromide, the nitrate, theperchlorate, the phosphate, the sulphate, the formate, the acetate, theaconate, the ascorbate, the benzenesulphonate, the benzoate, thecinnamate, the citrate, the embonate, the enantate, the fumarate, theglutamate, the glycolate, the lactate, the maleate, the malonate, themandelate, the methanesulphonate, the naphthalene-2-sulphonate derived,the phthalate, the salicylate, the sorbate, the stearate, the succinate,the tartrate, the toluene-p-sulphonate, and the like. Such salts may beformed by procedures well known and described in the art.

Metal salts of a 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative ofthe invention include alkali metal salts, such as the sodium salt of acompound of the invention containing a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradio-nuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), and combinations thereof.

Methods of Producing 1,4-Diaza-bicyclo[3.2.2]nonyl PyrimidineDerivatives

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the inventionmay be prepared by conventional methods for chemical synthesis, e.g.those described in the working examples. The starting materials for theprocesses described in the present application are known or may readilybe prepared by conventional methods from commercially availablechemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

The compounds of the invention are found to be cholinergic ligands atthe nicotinic acetylcholine receptors and modulators of the monoaminereceptors and transporters. In a more preferred embodiment the inventionis devoted to the provision novel ligands and modulators of thenicotinic receptors, which ligands and modulators are useful for thetreatment of diseases or disorders related to the cholinergic receptors,and in particular the nicotinic acetylcholine receptor (nAChR).Preferred compounds of the invention show a pronounced nicotinicacetylcholine α7 receptor subtype selectivity.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or conditions as diverse as CNSrelated diseases, PNS related diseases, diseases related to smoothmuscle contraction, endocrine disorders, diseases related toneuro-degeneration, diseases related to inflammation, pain, andwithdrawal symptoms caused by the termination of abuse of chemicalsubstances.

In a preferred embodiment the compounds of the present invention may beuseful for the treatment, prevention or alleviation of a cognitivedisorder, learning deficit, memory deficits and dysfunction, Down'ssyndrome, Alzheimer's disease, attention deficit, attention deficithyperactivity disorder (ADHD), Tourette's syndrome, psychosis,depression, Bipolar Disorder, mania, manic depression, schizophrenia,cognitive or attention deficits related to schizophrenia, obsessivecompulsive disorders (OCD), panic disorders, eating disorders such asanorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, autism, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, anxiety, non-OCDanxiety disorders, convulsive disorders, epilepsy, neurodegenerativedisorders, transient anoxia, induced neuro-degeneration, neuropathy,diabetic neuropathy, peripheral dyslexia, tardive dyskinesia,hyperkinesia, mild pain, moderate or severe pain, pain of acute, chronicor recurrent character, pain caused by migraine, postoperative pain,phantom limb pain, inflammatory pain, neuropathic pain, chronicheadache, central pain, pain related to diabetic neuropathy, topostherpetic neuralgia, or to peripheral nerve injury, bulimia,post-traumatic syndrome, social phobia, sleeping disorders,pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late lutealphase syndrome, fibromyalgia, chronic fatigue syndrome, mutism,trichotillomania, jet-lag, arrhythmias, smooth muscle contractions,angina pectoris, premature labour, diarrhoea, asthma, tardivedyskinesia, hyperkinesia, premature ejaculation, erectile difficulty,hypertension, inflammatory disorders, inflammatory skin disorders, acne,rosacea, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, diarrhoea, or withdrawal symptoms caused by termination of useof addictive substances, including nicotine containing products such astobacco, opioids such as heroin, cocaine and morphine, benzodiazepinesand benzodiazepine-like drugs, and alcohol.

In a more preferred embodiment the compounds of the invention may beuseful for the treatment, prevention or alleviation of pain, mild ormoderate or severe pain, pain of acute, chronic or recurrent character,pain caused by migraine, postoperative pain, phantom limb pain,inflammatory pain, neuropathic pain, chronic headache, central pain,pain related to diabetic neuropathy, to postherpetic neuralgia, or toperipheral nerve injury.

In an even more preferred embodiment the compounds of the invention maybe useful for the treatment, prevention or alleviation of diseases,disorders or conditions associated with smooth muscle contractions,convulsive disorders, angina pectoris, premature labour, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, or erectile difficulty.

In a still more preferred embodiment the compounds of the invention maybe useful for the treatment, prevention or alleviation of aneurodegenerative disorder, transient anoxia, or inducedneuro-degeneration.

In a yet more preferred embodiment the compounds of the invention may beuseful for the treatment, prevention or alleviation of an inflammatorydisorder, inflammatory skin disorder, acne, rosacea, Crohn's disease,inflammatory bowel disease, ulcerative colitis, or diarrhoea.

In a further preferred embodiment the compounds of the invention may beuseful for the treatment, prevention or alleviation of diabeticneuropathy, schizophrenia, cognitive or attentional deficits related toschizophrenia, or depression.

Finally the compounds of the invention may be useful for the treatmentof withdrawal symptoms caused by termination of use of addictivesubstances. Such addictive substances include nicotine containingproducts such as tobacco, opioids such as heroin, cocaine and morphine,benzodiazepines, benzodiazepine-like drugs, and alcohol. Withdrawal fromaddictive substances is in general a traumatic experience characterisedby anxiety and frustration, anger, anxiety, difficulties inconcentrating, restlessness, decreased heart rate and increased appetiteand weight gain.

In this context “treatment” covers treatment, prevention, prophylacticsand alleviation of withdrawal symptoms and abstinence as well astreatment resulting in a voluntary diminished intake of the addictivesubstance.

In another aspect, the compounds of the invention are used as diagnosticagents, e.g. for the identification and localisation of nicotinicreceptors in various tissues.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of the1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the invention.

While a 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of theinvention for use in therapy may be administered in the form of the rawcompound, it is preferred to introduce the active ingredient, optionallyin the form of a physiologically acceptable salt, in a pharmaceuticalcomposition together with one or more adjuvants, excipients, carriers,buffers, diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivative of the invention, or a pharmaceutically acceptable salt orderivative thereof, together with one or more pharmaceuticallyacceptable carriers therefore, and, optionally, other therapeutic and/orprophylactic ingredients, know and used in the art. The carrier(s) mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by any skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of theinvention, together with a conventional adjuvant, carrier, or diluent,may thus be placed into the form of pharmaceutical compositions and unitdosages thereof. Such forms include solids, and in particular tablets,filled capsules, powder and pellet forms, and liquids, in particularaqueous or non-aqueous solutions, suspensions, emulsions, elixirs, andcapsules filled with the same, all for oral use, suppositories forrectal administration, and sterile injectable solutions for parenteraluse. Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the presentinvention can be administered in a wide variety of oral and parenteraldosage forms. It will be obvious to those skilled in the art that thefollowing dosage forms may comprise, as the active component, either acompound of the invention or a pharmaceutically acceptable salt of acompound of the invention.

For preparing pharmaceutical compositions from a1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the presentinvention, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative according to thepresent invention may thus be formulated for parenteral administration(e.g. by injection, for example bolus injection or continuous infusion)and may be presented in unit dose form in ampoules, pre-filled syringes,small volume infusion or in multi-dose containers with an addedpreservative. The compositions may take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containformulation agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form,obtained by aseptic isolation of sterile solid or by lyophilization fromsolution, for constitution with a suitable vehicle, e.g. sterile,pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of the invention maybe formulated as ointments, creams or lotions, or as a transdermalpatch. Ointments and creams may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agents. Lotions may be formulated with an aqueous or oily baseand will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

The 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivatives of the presentinvention are valuable nicotinic and monoamine receptor modulators, andtherefore useful for the treatment of a range of ailments involvingcholinergic dysfunction as well as a range of disorders responsive tothe action of nAChR modulators.

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to modulation of cholinergic receptors and/ormonoamine receptors, and which method comprises administering to such aliving animal body, including a human, in need thereof an effectiveamount of a 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of theinvention.

In a preferred embodiment, the disease, disorder or condition relates tothe central nervous system.

The preferred medical indications contemplated according to theinvention are those stated above.

It is at present contemplated that suitable dosage ranges are within 0.1to 1000 milligrams daily, preferably 10 to 500 milligrams daily, andmore preferred of from 30 to 100 milligrams daily, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved, the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 Preparatory Example

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

1,4-Diazabicyclo[3.2.2]nonane (Intermediate compound)

The title compound was prepared according to J. Med. Chem. 1993 362311-2320 (and according to the slightly modified method describedbelow).

1,4-Diazabicyclo[3.2.2]nonane (Intermediate compound)

To the solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol)in absolute dioxane (130 ml) LiAlH₄ (4.9 g; 130 mmol) was added underargon. The mixture was refluxed for 6 h and then allowed to reach roomtemperature. To the reaction mixture water (5 ml in 10 ml of dioxane)was added by drops, the mixture was stirred for 0.5 hour and thenfiltered off via glass filter. The solvent was evaporated and theresidue was distilled using Kugelrohr apparatus at 90° C. (0.1 mbar) toyield 1,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourlesshygroscopic material.

1,4-Diazabicyclo[3.2.2]nonan-3-one (Intermediate compound)

To the solution of 3-quinuclidinone hydrochloride (45 g; 278 mmol) in 90ml of water hydroxylamine hydrochloride (21 g; 302 mmol) and sodiumacetate (CH₃COONa×3H₂O; 83 g; 610 mmol) were added, the mixture wasstirred at 70° C. for 1 hour and then cooled to 0° C. The separatedcrystalline material was filtered off (without washing) and dried invacuo to yield 40.0 g of oxime.

The 3-quinuclidinone oxime (40.0 g) was added during 2 hours by smallportions to preheated to 120° C. polyphosphoric acid (190 g). Thetemperature of the solution during the reaction was kept at 130° C.After addition of all oxime the solution was stirred for 20 minutes atthe same temperature, and was allowed to reach room temperature. Theacidic mixture was neutralized by a solution of potassium carbonate (500g in 300 ml of water), transferred into 2000 ml flask, diluted with 300ml of water and extracted with chloroform (3×600 ml). The combinedorganic extracts were dried with sodium sulphate, the solvent evaporatedand the solid residue dried up in vacuo to yield 30.0 g (77%) of themixture of lactams.

Crystallization of the obtained mixture from 1,4-dioxane (220 ml) gave15.8 g (40.5%) of 1,4-diazabicyclo[3.2.2]nonan-3-one as colourless largecrystals with mp. 211-212° C.

4-(5-Nitro-pyrimidin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane Free Base(Intermediate compound)

A mixture of 1,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol),2-chloro-5-nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) wasstirred at room-temperature for 15 h. Aqueous sodium bicarbonate (20 ml,10%) was added followed by extraction with ethylacetate (3×20 ml). Theorganic phase was dried and evaporated and a yellow powder was isolated.Yield 0.86 g (55%). Mp 135-139° C.

2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine Free Base(Intermediate compound)

A mixture of 4-(5-nitro-pyrimidin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane(0.71 g, 2.85 mmol), palladium (0.25 g, 10% on activated carbon) andmethanol (50 ml) was stirred under hydrogen for 10 min. Thereaction-mixture was filtered through celite and washed with ethanol (50ml). The product was dried and evaporated. Yield 100%.

Method A

3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-Quinazolin-4-onehydrochloride acid salt (Compound A1)

2-Amino-N-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-benzamide(0.85 g, 2.51 mmol) and formic acid (10 ml, 265 mmol) was stirred atreflux for 1 h. Aqueous ammonia was added followed by extraction withchloroform. The mixture was dried and evaporated The brown oil was mixedwith ethanol (25 ml) and hydrochloric acid (1 ml, 3 M). The mixture wascooled on an ice bath. The crystals were filtered and washed withethanol. Yield 0.41 g (42%). LC-ESI-HRMS of [M+H]+ shows 349.1776 Da.Calc. 349.177684 Da, dev. −0.2 ppm.

3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-Quinazolin-4-onefumaric acid salt (Compound A2)

Was prepared according to Method A. LC-ESI-HRMS of [M+H]+ shows 379.1893Da. Calc. 379.187704 Da, dev. 4.2 ppm.

Method B

3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-benzo[d][1,2,3]triazin-4-onehydrochloride acid salt (Compound B1)

A mixture of2-amino-N-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-benzamide(0.80 g, 2.36 mmol), acetic acid (10 ml) and water (2 ml) was cooled to5° C. and sodium nitrite (0.18 g, 2.6 mmol) solved in water (3 ml) wasadded. The mixture was stirred at 80° C. for 30 min. The mixture wasneutralized by adding ice and aqueous ammonia and extracted withchloroform. The mixture was dried and evaporated. The yellow oil wasmixed with ethanol (25 ml) and hydrochloric acid (1 ml, 3 M). Themixture was cooled on an ice bath. The crystals were filtered and washedwith ethanol followed by diethylether. Yield 0.52 g (57%). LC-ESI-HRMSof [M+H]+ shows 350.1732 Da. Calc. 350.172933 Da, dev. 0.8 ppm.

3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-benzo[d][1,2,3]triazin-4-onefumaric acid salt (Compound B2)

Was prepared according to Method B. LC-ESI-HRMS of [M+H]+ shows 380.1822Da. Calc. 380.182953 Da, dev. −2 ppm.

2-Amino-N-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-benzamide(Intermediate compound)

A mixture ofN-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-2-nitro-benzamide(4.0 g, 9.9 mmol), palladium on carbon (100 mg, 10%) and methanol (100ml) was stirred under hydrogen for 3 days. The mixture was neutralizedby adding aqueous ammonia and extracted with chloroform. The mixture wasdried and evaporated. The yellow oil was mixed with ethanol (25 ml) andhydrochloric acid (3 ml, 3 M). The mixture was cooled on an ice bath.The crystals were filtered and washed with ethanol followed bydiethylether. Yield 2.27 g (61%).

N-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-2-nitro-benzamidehydrochloric acid salt (Intermediate compound)

A mixture of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylaminefree base and THF (275 ml) was added to another mixture of2-nitrobenzoylchloride (10 g, 53.9 mmol) during 45 minutes. The mixturewas stirred at room temperature for 15 h. The crystals were filtered andwashed with THF. The crystals where boiled in ethanol (100 ml, 96%) andthe mixture was stored in the refrigerator for 3 hours. The crystalswere filtered and washed with ethanol followed by diethylether. Yield6.47 g (33%). LC-ESI-HRMS of [M+H]+ shows 369.169 Da. Calc. 369.167514Da, dev. 4 ppm.

Example 2

In vitro Inhibition of ³H-α-Bungarotoxine Binding in Rat Brain

The affinity of a compound for binding to α-subtype of nicotinicreceptors may be determined in a standard assay carried out essentiallyas described in e.g. WO 2006/087306. In this assay the test value ispresented as an IC₅₀ (the concentration of the test substance whichinhibits the specific binding of ³H-α-bungarotoxin by 50%).

Compounds of the invention tested in this assay show activities in thelow micromolar range, in particular below 10 μM. Most preferredcompounds of the invention show activities in the sub-micromolar range(i.e. having an IC₅₀ of below 1 μM).

1-9. (canceled)
 10. A 1,4-diaza-bicyclo[3.2.2]nonyl pyrimidinederivative represented by Formula I

a stereoisomer thereof or a mixture of its stereoisomers, or apharmaceutically acceptable salt thereof; wherein X represents N or CH;and R¹ and R², independently of each other, represent hydrogen, halo,trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy,alkyl-sulfonyl, phenyl or phenoxy.
 11. The 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of claim 10, a stereoisomer thereof or a mixtureof its stereoisomers, or a pharmaceutically acceptable salt thereof,wherein X represents N or CH.
 12. The 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of claim 10, a stereoisomer thereof or a mixtureof its stereoisomers, or a pharmaceutically acceptable salt thereof,wherein R¹ and R², independently of each other, represent hydrogen,halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy,alkyl-sulfonyl, phenyl or phenoxy.
 13. The 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of claim 10, which is3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-quinazolin-4-one;3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-benzo[d][1,2,3]triazin-4-one;3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-quinazolin-4-one;or3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-7-methoxy-3H-benzo[d][1,2,3]triazin-4-one;a stereoisomer thereof or a mixture of its stereoisomers, or apharmaceutically acceptable salt thereof.
 14. The1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of claim 10, whichis3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-benzo[d][1,2,3]triazin-4-one;or a pharmaceutically acceptable salt thereof.
 15. The1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of claim 10, whichis 3-[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-yl]-3H-benzo[d][1,2,3]triazin-4-one hydrochloride acid salt.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of the1,4-diaza-bicyclo[3.2.2]nonyl pyrimidine derivative of claim 10, astereoisomer thereof or a mixture of its stereoisomers, or aphaimaceutically-acceptable salt thereof, together with at least onepharmaceutically-acceptable carrier or diluent.
 17. A method oftreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to modulation of cholinergicreceptors and/or monoamine receptors, which method comprises the step ofadministering to such a living animal body in need thereof atherapeutically effective amount of the 1,4-diaza-bicyclo[3.2.2]nonylpyrimidine derivative of claim 10, a stereoisomer thereof or a mixtureof its stereoisomers, or a pharmaceutically acceptable salt thereof. 18.The method according to claim 17, wherein the disease, disorder orcondition is a cognitive disorder, learning deficit, memory deficits anddysfunction, Down's syndrome, Alzheimer's disease, attention deficit,attention deficit hyperactivity disorder (ADHD), Tourette's syndrome,psychosis, depression, Bipolar Disorder, mania, manic depression,schizophrenia, cognitive or attention deficits related to schizophrenia,obsessive compulsive disorders (OCD), panic disorders, eating disorderssuch as anorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, autism, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, anxiety, non-OCDanxiety disorders, convulsive disorders, epilepsy, neurodegenerativedisorders, transient anoxia, induced neuro-degeneration, neuropathy,diabetic neuropathy, peripheral dyslexia, tardive dyskinesia,hyperkinesia, mild pain, moderate or severe pain, pain of acute, chronicor recurrent character, pain caused by migraine, postoperative pain,phantom limb pain, inflammatory pain, neuropathic pain, chronicheadache, central pain, pain related to diabetic neuropathy, topostherpetic neuralgia, or to peripheral nerve injury, bulimia,post-traumatic syndrome, social phobia, sleeping disorders,pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late lutealphase syndrome, fibromyalgia, chronic fatigue syndrome, mutism,trichotillomania, jet-lag, arrhythmias, smooth muscle contractions,angina pectoris, premature labour, diarrhoea, asthma, tardivedyskinesia, hyperkinesia, premature ejaculation, erectile difficulty,hypertension, inflammatory disorders, inflammatory skin disorders, acne,rosacea, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, diarrhoea, or withdrawal symptoms caused by termination of useof addictive substances, including nicotine containing products such astobacco, opioids such as heroin, cocaine and morphine, benzodiazepinesand benzodiazepine-like drugs, and alcohol.